Lupus and the Kidney
Dr James Pattison DM FRCP, Consultant Nephrologist, Guy's and St Thomas' NHS Foundation Trust
In 1900 Sir William Osler first described renal disease in patients with SLE. In 1922 Keith and Rowntree published the autopsy findings in the kidneys of lupus patients. Renal biopsies were first performed in the 1950s and Kark and Muehrke in a landmark paper in 1957 described the histological features of lupus nephritis. In 1950 corticosteroids were given for the first time to a patient with lupus. Cyclophosphamide became the standard treatment for induction for severe lupus nephritis in the 1970s, with prednisolone and azathioprine being used for maintenance. The mortality from lupus nephritis has dramatically fallen since these treatments have been used, and since dialysis and transplantation became available to treat end-stage renal failure. However corticosteroids and cyclophosphamide can cause major side-effects, and newer agents such as mycophenolate mofetil (MMF) and rituximab offer the promise of fewer complications.
In general the primary target for lupus in the kidneys are the glomeruli. Inflammation in the glomeruli eventually leads to scarring in the renal tubules. In lupus patients who have antiphospholipid antibodies the primary site of renal injury may be the renal vessels. Percutaneous renal biopsy is performed to define the grade of lupus nephritis, and also to assess the activity of the disease and the degree of permanent renal damage. The renal biopsy helps to guide the decision about the appropriate treatment in each individual case. In some patients it may lead to reduction of immunosuppression. Patients are routinely monitored by measuring the serum creatinine which is a marker of renal function, protein excretion rates and markers of lupus activity such as dsDNA and complement levels. Novel non-invasive techniques for assessing activity of lupus nephritis include measuring urinary chemokine levels.
In general lupus tends to affect the kidneys of younger patients. In the Eurolupus study evidence of lupus nephritis was present in 16% of patients at presentation and in 39% of cases at some point during their life. Lupus nephritis can present either with traces of blood and protein in the urine, large degrees of proteinuria causing ankle swelling (nephrotic syndrome) or hypertension and acute renal failure. Risk factors for poor outcome include raised creatinine at presentation, heavy proteinuria, male gender, young age, black ethnicity, class 4 appearances on biopsy and multiple renal flares.
Patients with mild lupus nephritis (less than 1g/day proteinuria, normal creatinine) should be followed up to ensure that the nephritis is not worsening, and in general do not need specific treatment. Patients with class 5 (membranous) lupus nephritis usually have heavy proteinuria and oedema and are managed with diuretics, cholesterol lowering drugs and ACE inhibitors. In some cases it may be appropriate to use immunosuppressive drugs.
Patients with class 3 and 4 (proliferative) lupus nephritis will be given immunosuppressive drugs. The treatment choices are controversial. A meta-analysis of 19 trials confirm that the outcome is better when either cyclophosphamide, azathioprine or MMF are given in conjunction with steroids compared to using steroids alone. Until recently most severe cases have been given high dose steroids and intravenous cyclophosphamide as induction with maintenance treatment consisting of prednisolone and azathioprine. The principle problem with cyclophosphamide is that extended courses can cause gonadal failure leading to infertility and premature menopause in women. As most patients with severe lupus nephritis are women of child-bearing age this is a major limitation.
Therefore the advent of studies comparing MMF with cyclophosphamide has been greeted with much interest. Chan in 2000 published a study in which 42 patients with relatively mild lupus nephritis in Hong Kong were randomised to either 12 months prednisolone and MMF or 6 months prednisolone and cyclophosphamide followed by 6 months prednisolone and azathioprine. Both treatment options were equally efficacious. In 2004 Conteras published a study in which 59 American patients who had gone into remission after receiving 4-6 months intravenous cyclophosphamide were randomised to receive either 3 monthly intravenous cyclophosphamide, azathioprine or MMF. The MMF group had the best results in terms of efficacy and safety. In 2005 Ginzler reported a study in which 140 American patients with moderately severe lupus nephritis were randomised to receive either MMF or monthly intravenous cyclophosphamide. There were more responses to treatment in the MMF group, and fewer serious infections and deaths. In summary MMF appears to be a good alternative to cyclophosphamde in all but the most severe cases of lupus nephritis. It is particularly attractive in patients in whom fertility is an issue. Further studies (LUNAR, ALMS and EURO-LUPUS) are underway to assess the efficacy of various MMF based regimens.
Other treatments which can be used in cases of severe lupus nephritis include plasma exchange, intravenous immunoglobulin and rituximab. Rituximab is a monoclonal antibody which kills antibody producing B cells. Isenberg in 2005 published a series of 24 cases of severe lupus refractory to other treatments in whom rituximab was administered. The results were encouraging with prolonged remissions in some cases.
Lupus patients with nephritis and antiphospholipid antibodies are at risk of developing damage to all sizes of large renal vessels including renal artery stenoses and renal vein thromboses, and the microvasculature. They should be anticoagulated with warfarin.
Lupus patients who develop end-stage renal failure are managed either by dialysis or renal transplantation. In general the systemic symptoms of lupus improve in patients with renal failure probably because of the immunosuppressive effect of kidney failure itself. A few patients may recover renal function several months after starting dialysis. Patients can be managed either by haemodialysis or peritoneal dialysis. Haemodialysis involves being connected to a dialysis machine three times a week. It is usually carried out in a dialysis unit but some patients can dialyse themselves at home. Peritoneal dialysis is done at home and involves dialysis fluid being exchanged through a tube inserted into the abdomen. The exchanges can be done manually or automatically by a machine. Whether haemodialysis or peritoneal dialysis is superior depends on each individual's circumstances. The optimal treatment for end-stage renal failure is renal transplantation ideally from a live-donor. The results are superior from live-donors compared to deceased donors. There is a shortage of deceased donor kidneys and an increasing number of potential recipients, and as a result waiting times for renal transplanatation have increased to about 4-5years. In general lupus nephritis rarely recurs after renal transplantation. Patients with antiphospholipid antibodies are at increased risk of thrombosing the transplant and therefore need to be anticoagulated.
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